Cancer is associated with the abnormal growth of cells which proliferate uncontrollably and can metastasize into surrounding tissues. There are over 200 types of cancer and distinct subtypes have been identified. Adding to the challenging complexities of cancer, is intra-tumoral variability, where tumours contain more than one type of cancer cell. This variability often reduces the efficacy of existing therapies, compromising patient outcomes.
There is a growing interest in the field of Precision Medicine where the focus is on patient-specific therapies, so that such challenges like intra-tumoral variability can be overcome through the development of specialized treatments. In contrast, a project at the Vall d’Hebron Institute of Oncology has been researching and developing a more universal approach, that could target different types of cancer.
Ximbio spoke to Dr. Laura Soucek, the project’s lead researcher to find out more.
Targeting a protein common across all cancers
Dr. Soucek entered research with one goal in mind – to make a difference in cancer research. To that end, she decided to focus on targeting a protein that was, and still is, considered by many to be “undruggable” – Myc. The Myc protein sits within the nuclei and acts as a ‘master regulator’ of a variety of cellular functions, including proliferation, differentiation, metabolism, and survival. Due to its multidimensional role, it is critical for Myc to be tightly regulated. Deregulation of Myc leads to altered cellular proliferation and growth, protein synthesis, and metabolism. Additionally, Myc promotes tumour progression through activation of angiogenesis and suppression of the host immune system. However, Myc is a difficult target for cancer therapy. Its location within the nuclei, together with its intrinsically disordered structure and lack of a specific active site, make direct Myc inhibition with traditional strategies challenging. Moreover, all three Myc family members (MYC, MYCN, and MYC) need to be targeted to obtain the most efficient therapeutic impact.
A long road to success
For 20 years, Dr. Soucek has been researching ways to inhibit Myc. In 1998, Dr. Soucek designed the dominant-negative form of Myc called Omomyc, as a laboratory tool to study Myc biology. Since then, many milestones have been achieved; First using in vitro systems, transgene expression of Omomyc inhibited Myc expression in normal and cancer cells. Later, in various animal models of cancer, Myc inhibition by Omomyc exerted remarkable anti-cancer properties, without adverse and irreversible effects.
“When we turned off Myc in cancer cells using Omomyc, we saw that it had a dramatic therapeutic effect in different types of experimental cancer models. The beauty of it is that, while everybody expected normal proliferating cells to suffer too, they simply slowed down their proliferation, but nothing major happened to them. So, we finally had a tool against cancer that seemed not to cause any severe side effects in normal proliferating tissues. And the other thing that really made me happy was that it appeared to be the opposite of personalised medicine: We had a technology that would be applicable to all types of cancers, so that maybe we didn't need different drugs for each of them, maybe we could use a common one for all cancers and patients.”
Images of mouse tissues expressing transgenic Omomyc. Sections of normal pancreas tissue and mammary tumours were stained with a monoclonal Omomyc antibody (clone 21-1-3, available from Ximbio) shown in green, with nuclear counterstaining in blue (DAPI). Images kindly provided by Dr Jonathan Whitfield and Dr Laura Soucek.
A potential new treatment
After the promising results obtained in vitro and in vivo, the next step was the conversion of Omomyc to an administrable drug. Dr. Soucek and her team showed that, as an alternative to its use as a transgene, Omomyc could be produced as a recombinant mini-protein. In fact, her most recent studies showed that the purified Omomyc mini-protein itself spontaneously penetrates cancer cells and effectively interferes with MYC transcriptional activity, both in vitro and in vivo.
Currently, this Omomyc-based protein is entering clinical trials, where it will be tested for safety and efficacy in non-small-cell lung cancer, triple negative breast cancer and colorectal cancer. However, this isn’t the end of the journey for Dr. Soucek. Cancer treatments are needed for many more types of cancer, so Dr. Soucek and her team plan on developing products for other oncological indications too.
“My pet project from the very beginning was targeting Myc and even though everybody told me that I couldn't do it, now we know we can. We now have a pharmacological tool that is entering clinical trials for the first time. So, that for me is still my major pride in all these adventures.”